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Targeting macrophages in the elderly improves response to cancer immunotherapy and reduces treatment-associated cachexia

Lelinh Duong (1), Hannah Radley-Crabb (1), Danielle Dye (1), Miranda Grounds (2), Delia Nelson (1) and Connie Jackaman (1)

  1. School of Biomedical Sciences, Curtin Health Innovation Research Institute, Bentley, Western Australia, Australia

  2. School of Anatomy and Human Biology, University of Western Australia, Perth, Western Australia, Australia

Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. The immune system plays a critical role in the effectiveness of many anti-cancer therapies in young hosts via tumour-specific T cells. However, macrophages can constitute up to 50% tumour burden and impair anti-tumour T cell activity via their inflammatory function. It is unknown if this occurs during anti-cancer immunotherapy in the elderly. Therefore, we examined young (3 months, cf. 18 human years) and elderly (22-24 months, cf. 65-70 human years) AE17 mesothelioma-bearing C57BL/6J mice treated with intra-tumoural IL-2/anti-CD40 immunotherapy. Faster progressing tumours in elderly relative to young mice was associated with increased tumour-associated macrophages, increased pro-inflammatory cytokines and worsened cancer cachexia. Immunotherapy was also less effective in elderly (45% tumour regression) compared to young mice (100% regression) and was associated with decreased in vivo anti-tumour cytotoxic T cell activity. Interestingly, targeting of macrophages using anti-F4/80 antibody in elderly, but not young mice, improved cancer immunotherapy leading to 78% tumour regression. This also increased in vivo anti-tumour T cell activity in elderly, but not young mice. All tumour-bearing elderly (but not young) mice had decreased body weight (i.e. exhibited cachexia), which was greatly exacerbated by immunotherapy. Whereas macrophage blockade prevented this immunotherapy-induced cachexia and reduced inflammation in the elderly mice. These studies strongly indicate that age-related changes in macrophages play a key role in driving cancer cachexia in the elderly, particularly during immunotherapy, and sabotage elderly anti-tumour immune responses. Our studies suggest that macrophages are key drivers of inflammatory dysregulation in the elderly and strategies to target these cells could help to reduce inflammation; one of the seven "Pillars of Ageing".